Multidrug brittle matrix compositions

Abstract

Dual and triple therapy combinations of drugs formulated as brittle matrix particles with a high surface area are provided herein. These particle formulations may be used in inhalation or aerosol administration techniques to provide the drug combinations to the lungs. In some aspects, these compositions may be used to treat a respiratory disease or disorder such as asthma or COPD.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising either:
 a. a triple therapy comprising a therapeutically effective amount of an active pharmaceutical ingredient from each of the following groups:
 i. a long acting β-agonist (LABA); 
 ii. a long acting muscarinic antagonist (LAMA); and 
 iii. a cortiscosteroid (CS); or 
   b. a dual therapy comprising a therapeutically effective amount of an active pharmaceutical ingredient from both of the following groups:
 i. a long acting β-agonist (LABA), and 
 ii. a corticosteroid (CS); 
   
       wherein the pharmaceutical composition is formulated as a brittle matrix particle having a specific surface area of greater than 5 m 2 /g. 
     
     
         2 . The pharmaceutical composition of  claim 1  further comprising one or more excipients. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the excipient is a sugar, sugar derivative, or an amino acid. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the excipient is a sugar or a sugar derivative. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the excipient is lactose, mannitol, or trehalose. 
     
     
         6 . The pharmaceutical composition of  claim 2 , wherein the excipient is an amino acid. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the excipient is glycine. 
     
     
         8 . The pharmaceutical composition according to any one of  claims 1 - 7 , wherein the long acting β-agonist is a salmeterol or formoterol salt. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the long acting β-agonist is salmeterol xinafoate. 
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein the long acting β-agonist is formoterol fumarate. 
     
     
         11 . The pharmaceutical composition according to any one of  claims 1 - 10 , wherein corticosteroid is mometasene furoate or budesomide. 
     
     
         12 . The pharmaceutical composition according to any one of  claims 1 - 11 , wherein the long acting muscarinic antagonist is a tiotropium salt. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the long acting muscarinic antagonist is tiotropium bromide. 
     
     
         14 . The pharmaceutical composition according to any one of  claims 1 - 13 , wherein the dual therapy comprises a weight ratio of the long acting β-agonist to the corticosteroid from about 1:0.1 to about 1:100 in the composition. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the dual therapy has a weight ratio of about 5:22 of the long acting β-agonist to the corticosteroid. 
     
     
         16 . The pharmaceutical composition according to any one of  claims 1 - 12 , wherein the triple therapy comprises a weight ratio of the long acting β-agonist to the long acting muscarinic antagonist to the corticosteroid from about 1:0.1:0.1 to about 1:100:100 in the composition. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the triple therapy weight ratio is about 1:2:35.5 of the long acting β-agonist to the long acting muscarinic antagonist to the corticosteroid. 
     
     
         18 . The pharmaceutical composition according to any one of  claims 1 - 12 ,  16 , or  17 , wherein the triple therapy comprises a weight ratio of the long acting β-agonist to the long acting muscarinic antagonist from about 1:0.1 to about 1:100 in the composition. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the triple therapy weight ratio is about 1:2 of the long acting β-agonist to the long acting muscarinic antagonist. 
     
     
         20 . The pharmaceutical composition according to any one of  claims 1 - 12  or  16 - 19 , wherein the triple therapy comprises a weight ratio of the long acting β-agonist to the corticosteroid from about 1:0.1 to about 1:100 in the composition. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the triple therapy weight ratio is about 2:70 of the long acting β-agonist to the corticosteroid. 
     
     
         22 . The pharmaceutical composition according to any one of  claims 1 - 12  or  16 - 21 , wherein the triple therapy comprises a weight ratio of the long acting muscarinic antagonist to the corticosteroid from about 1:0.1 to about 1:1000 in the composition. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the triple therapy weight ratio is about 4:70 of the long acting muscarinic antagonist to the corticosteroid. 
     
     
         24 . The pharmaceutical composition according to any one of  claims 1 - 23 , wherein the pharmaceutical composition has a molar ratio of the dual therapy or the triple therapy to the excipient of from about 1:0 to about 1:9 in the composition. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the molar ratio is about 1:1 of the dual therapy or the triple therapy to the excipient. 
     
     
         26 . The pharmaceutical composition according to any one of  claims 1 - 25 , wherein the pharmaceutical composition is formulated as a unit dose. 
     
     
         27 . The pharmaceutical composition according to any one of  claims 1 - 25 , wherein the unit dose of the pharmaceutical composition comprises a dose of the long acting β-agonist from about 1 to about 500 μg. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the dose of the long acting β-agonist is about 50 μg when the long acting β-agonist is salmeterol xinafoate. 
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein the dose of the long acting β-agonist is about 4.5 μg when the long acting β-agonist is formoterol fumarate. 
     
     
         30 . The pharmaceutical composition according to any one of  claims 1 - 25 , wherein the unit dose of the pharmaceutical composition comprises a dose of the long acting muscarinic antagonist from about 1 to about 100 μg. 
     
     
         31 . The pharmaceutical composition of  claim 27 , wherein the dose of the long acting muscarinic antagonist is about 9 μg. 
     
     
         32 . The pharmaceutical composition according to any one of  claims 1 - 25 , wherein the unit dose of the pharmaceutical composition comprises a dose of the corticosteroid from about 1 to about 1000 μg. 
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the dose of the corticosteroid is about 220 μg when the corticosteroid is mometasene furoate. 
     
     
         34 . The pharmaceutical composition of  claim 32 , wherein the dose of the corticosteroid is about 160 μg when the corticosteroid is budesomide. 
     
     
         35 . The pharmaceutical composition according to any one of  claims 1 - 33 , wherein the pharmaceutical composition is formulated for administration: intranasally, via aerosol, to the lungs, or via inhalation. 
     
     
         36 . The pharmaceutical composition according to any one of  claims 1 - 33 , wherein the pharmaceutical composition is formulated for use in an inhaler. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the inhaler is a metered dose inhaler, a dry powder inhaler, a single dose inhaler, multi-unit dose inhaler, nebulizer, or pressurized metered dose inhaler. 
     
     
         38 . The pharmaceutical composition according to any one of  claims 1 - 37 , wherein the pharmaceutical composition is the dual therapy comprising salmeterol xinafoate and mometasene furoate. 
     
     
         39 . The pharmaceutical composition according to any one of  claims 1 - 37 , wherein the pharmaceutical composition is the triple therapy comprising formoterol fumarate, tiotropium bromide, and budesomide. 
     
     
         40 . The pharmaceutical composition according to any one of  claims 1 - 39 , wherein the pharmaceutical composition has a specific surface area from about 5 m 2 /g to about 1000 m 2 /g. 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the pharmaceutical composition has a specific surface area from about 10 m 2 /g to about 500 m 2 /g. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the pharmaceutical composition has a specific surface area from about 20 m 2 /g to about 250 m 2 /g. 
     
     
         43 . The pharmaceutical composition according to any one of  claims 1 - 42 , wherein the pharmaceutical composition has a total emitted dose (TED) of greater than 85%. 
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein the total emitted dose (TED) is from about 90% to about 100%. 
     
     
         45 . The pharmaceutical composition according to any one of  claims 1 - 44 , wherein the pharmaceutical composition is free of any impurities. 
     
     
         46 . The pharmaceutical composition according to any one of  claims 1 - 45 , wherein the pharmaceutical composition is essentially free of polyvinylpyrrolidone, polyvinylalcohol, polyacrylate, or polystyrene. 
     
     
         47 . The pharmaceutical composition according to any one of  claims 1 - 46 , wherein the pharmaceutical composition is essentially free of any polymeric excipients. 
     
     
         48 . The pharmaceutical composition according to any one of  claims 1 - 47 , wherein the pharmaceutical composition is essentially free of poloxamers, polyethylene glycol, or polypropylene glycol. 
     
     
         49 . The pharmaceutical composition according to any one of  claims 1 - 48 , wherein the pharmaceutical composition is essentially free of any surfactants. 
     
     
         50 . The pharmaceutical composition according to any one of  claims 1 - 44 , wherein the pharmaceutical composition is free of other compounds beyond the excipient and the active pharmaceutical composition. 
     
     
         51 . A method of treating or preventing a respiratory disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of  claims 1 - 39 . 
     
     
         52 . The method of  claim 51 , wherein the respiratory disease or disorder is a disorder involving inflammation of the lungs or sinuses. 
     
     
         53 . The method of  claim 51 , wherein the respiratory disease or disorder is asthma. 
     
     
         54 . The method of  claim 51 , wherein the respiratory disease or disorder is chronic obstructive pulmonary disease. 
     
     
         55 . The method according to any one of  claims 51 - 54 , wherein the pharmaceutical composition is administered via inhalation. 
     
     
         56 . The method of  claim 55 , wherein the therapeutically effective amount is administered to the patient in one inhalation. 
     
     
         57 . The method of  claim 55 , wherein the therapeutically effective amount is administered to the patient in 2 or more inhalations. 
     
     
         58 . The method of  claim 57 , wherein the therapeutically effective amount is administered in 2, 3, or 4 inhalations. 
     
     
         59 . The method according to any one of  claims 51 - 58 , wherein the method comprises administering the therapeutically effective amount to the patient once a day. 
     
     
         60 . The method according to any one of  claims 51 - 58 , wherein the method comprises administering the therapeutically effective amount to the patient two or more times a day. 
     
     
         61 . A method of preparing a brittle matrix pharmaceutical composition comprising:
 (A) admixing two or more active pharmaceutical agents into a solvent wherein the solvent comprises an organic solvent and water to form a pharmaceutical composition wherein the pharmaceutical composition comprises an amount of the active pharmaceutical agents in the solvent from about 0.01% to about 10% (w/v);   (B) applying the pharmaceutical composition to a rotating surface wherein the surface is at a temperature from about −70° C. to about −120° C.; and   (C) freezing the pharmaceutical composition to form a brittle matrix pharmaceutical composition.   
     
     
         62 . The method of  claim 61 , wherein the active pharmaceutical ingredients are selected from a long acting β-agonist, a long acting muscarinic antagonist, and a corticosteroid. 
     
     
         63 . The method of  claim 61  or  claim 62 , wherein the pharmaceutical composition further comprises one or more excipients. 
     
     
         64 . The method according to any one of  claims 61 - 63 , wherein the method further comprises lyophilizing the brittle matrix pharmaceutical composition. 
     
     
         65 . The method according to any one of  claims 61 - 64 , wherein the amount is from about 0.01% (w/v) to about 6% (w/v). 
     
     
         66 . The method of  claim 65 , wherein the amount is from about 0.1% (w/v) to about 5% (w/v). 
     
     
         67 . A pharmaceutical composition prepared according to the method of  claim 61 .